Effect of Anti-Macrophage Migration Inhibitory Factor Antibody on Lipopolysaccharide-induced  Pulmonary Neutrophil Accumulation

170

155

Macrophage migration inhibitory factor (MIF) was originally identified for its ability to inhibit the random migration of macrophages in vitro. MIF is now recognized as an important mediator in a range of inflammatory disorders. We recently observed that the absence of MIF is associated with a reduction in leukocyte-endothelial cell interactions induced by a range of inflammatory mediators, suggesting that one mechanism whereby MIF acts during inflammatory responses is by promoting leukocyte recruitment. However, it is unknown whether MIF is capable of inducing leukocyte recruitment independently of additional inflammatory stimuli. In this study, we report that MIF is capable of inducing leukocyte adhesion and transmigration in postcapillary venules in vivo. Moreover, leukocytes recruited in response to MIF were predominantly CD68+ cells of the monocyte/macrophage lineage. Abs against the monocyte-selective chemokine CCL2 (JE/MCP-1) and its receptor CCR2, but not CCL3 and CXCL2, significantly inhibited MIF-induced monocyte adhesion and transmigration. CCL2−/− mice displayed a similar reduction in MIF-induced recruitment indicating a critical role of CCL2 in the MIF-induced response. This hypothesis was supported by findings that MIF induced CCL2 release from primary microvascular endothelial cells. These data demonstrate a previously unrecognized function of this pleiotropic cytokine: induction of monocyte migration into tissues. This function may be critical to the ability of MIF to promote diseases such as atherosclerosis and rheumatoid arthritis, in which macrophages are key participants.

Section: Discussionmentioning

confidence: 70%

“…Previous studies have suggested a role for MIF in regulation of chemokine expression. MIF blockade has previously been shown to reduce CXCL2/MIP-2 expression in lungs of LPS-treated mice (26). Moreover, MIF has also been shown to increase expression of chemokines in neuroblastoma cell lines, human alveolar cells, and mouse lungs FIGURE 9.…”

Section: Discussionmentioning

confidence: 96%

Macrophage Migration Inhibitory Factor Induces Macrophage Recruitment via CC Chemokine Ligand 2

Gregory

Morand

McKeown

et al. 2006

170

155

“…5) and is commonly expressed in liver and other tissues (45) as an inflammatory cytokine that can also induce TNF-␣ (46). Studies with anti-MIF Ab demonstrate a protective effect in models of endotoxin-induced injury (47). After 4 wk of dietary treatment with or without ethanol, a mild inflammatory infiltration was observed in mice receiving a high-fat control diet.…”

Section: Cytokinesmentioning

confidence: 97%

Reduced Early Alcohol-Induced Liver Injury in CD14-Deficient Mice

Yin

Bradford

Wheeler

et al. 2001

225

125

Activation of Kupffer cells by gut-derived endotoxin is associated with alcohol-induced liver injury. Recently, it was shown that CD14-deficient mice are more resistant to endotoxin-induced shock than wild-type controls. Therefore, this study was designed to investigate the role of CD14 receptors in early alcohol-induced liver injury using CD14 knockout and wild-type BALB/c mice in a model of enteral ethanol delivery. Animals were given a high-fat liquid diet continuously with ethanol or isocaloric maltose-dextrin as control for 4 wk. The liver to body weight ratio in wild-type mice (5.8 ± 0.3%) was increased significantly by ethanol (7.3 ± 0.2%) but was not altered by ethanol in CD14-deficient mice. Ethanol elevated serum alanine aminotransferase levels nearly 3-fold in wild-type mice, but not in CD14-deficient mice. Wild-type and knockout mice given the control high-fat diet had normal liver histology, whereas ethanol caused severe liver injury (steatosis, inflammation, and necrosis; pathology score = 3.8 ± 0.4). In contrast, CD14-deficient mice given ethanol showed minimal hepatic changes (score = 1.6 ± 0.3, p < 0.05). Additionally, NF-κB, TGF-β, and TNF-α were increased significantly in wild-type mice fed ethanol but not in the CD14 knockout. Thus, chronic ethanol feeding caused more severe liver injury in wild-type than CD14 knockouts, supporting the hypothesis that endotoxin acting via CD14 plays a major role in the development of early alcohol-induced liver injury.

“…It has been implicated in the pathogenesis of a number of inflammatory disorders including sepsis, acute respiratory distress syndrome (in adults), asthma, and inflammatory/autoimmune diseases (16 -20). Within the lung, MIF is expressed in bronchial epithelial cells, alveolar macrophages, alveolar endothelium, and in the monocytes and eosinophils isolated by bronchial alveolar lavage (17,18,21). MIF has a role in the pathogenesis of endotoxic shock, and it is known to up-regulate TLR4, which transduces the signals of endotoxins (16,22).…”

mentioning

confidence: 99%

A Role for Macrophage Migration Inhibitory Factor in the Neonatal Respiratory Distress Syndrome

Kevill

Bhandari

Kettunen

et al. 2008

Using a mouse model of neonatal respiratory distress syndrome (RDS), we demonstrate a central role for macrophage migration inhibitory factor (MIF) in lung maturation at the developmental stage when human neonates are most susceptible to RDS. We prematurely delivered mouse pups at embryonic day 18, during the early saccular stage of pulmonary development. Only 8% of the prematurely delivered pups genetically deficient in MIF survived 8 h vs 75% of wild-type controls (p < 0.001). This phenotype was corrected when pups of all genotypes were bred from dams heterozygote for MIF deficiency. Local production of MIF in the lung increased at embryonic day 18, continued until full-term at embryonic day 19.5, and decreased in adulthood, thus coinciding with this developmental window. The lungs of pups genetically deficient in MIF were less mature upon histological evaluation, and demonstrated lower levels of vascular endothelial growth factor and corticosterone – two factors that promote fetal lung maturation. In vitro studies support a role for MIF in surfactant production by pulmonary epithelial cells. In a cohort of human neonates with RDS, higher intrapulmonary MIF levels were associated with a lower likelihood of developing bronchopulmonary dysplasia, a sequelae of RDS (p < 0.03). This study demonstrates for the first time a role for MIF in lung maturation, and supports a protective role for MIF in newborn lung disease.